Orally administered contrast agents for cholecystography

ABSTRACT

1. A COMPOUND WHICH IS A 3-(3-ACYAMINO-2,4,6-TRIIODOPHENOXY)-ALKOXY)-2-ALKYLPROPIONIC ACID OF THE FORMULA   1-(HOOC-CH(-R&#39;&#39;)-CH2-O-(CH2)N-O-),2,4,6-TRI(I-),3-(R-NH-)-   CYCLOHEXANE   OR A WATER-SOLUBLE SALT OF SAID ACID WITH A PHYSIOLOGICALLY TOLERATED METAL OR AMINE, IN SAID FORMULA R BEING ACETYL OR PROPIONYL, R&#39;&#39; BEING METHYL OR ETHYL, AND N BEING AN INTEGER BETWEEN 2 AND 4.

Filed Nov. 26. 1971 FIGJ E. FELDER ET AL ORALLY ADMINISTERED CONTRASTAGENTS FOR CHOLECYSTOGRAPHY 2 Sheets-Sheet I 24 HOURS MlCROMOLE/WLQINVENTORS.

ERNST FELDER'E DAVIDE PITRE Wm M y W M AGENTS Oct. 15, 1974 FELDER ET AL3,842,124

ORALLY ADHINISTERED CONTRAST AGENTS FUR CHOLECYSTOGRAPHY Filed Nov. 26,1971 2 Sheets-Sheet 2 O O (O Y 2 ll.

I I l I I O O O O O INVENTORS. o 9 co 0 v N ERNST FELDER 8 DAVIDE'PITREAGENTS United States Patent 3,842,124 ORALLY ADMINISTERED CONTRASTAGENTS FOR CHOLECYSTOGRAPHY Ernst Felder and Davide Pitre, Milan, Italy,assignors to Bracco Industria Chimica, Societa per Azioni, Milan,

Italy Filed Nov. 26, 1971, Ser. No. 202,381 Claims priority, applicationSwitzerland, Dec. 15, 1970, 18,621/ 70 Int. Cl. C07c 101/72 US. Cl.260501.11 6 Claims ABSTRACT OF THE DISCLOSURE 3- [2-3-Acetylamino-2,4,'6-triiodophenoxy) -ethoxy] 2- ethylpropionic acid andits physiologically tolerated salts are safe and effective contrastagents for oral administration prior to cholecystography. Homologs inwhich acetyl is replaced by propionyl, and ethoxy is replaced by propoxyor butoxy, are moderately inferior, but are also useful forcholecystography.

This invention relates to contrast agents for use in cholecystography,and particularly to new radiopaque compounds, their synthesis, and theiruse in cholecystography by oral administration.

The requirements for contrast agents to be employed in cholecystographyby oral administration are complex. They include (1) preferentialsecretion from the liver into the gall bladder as compared to secretionfrom the kidney into the urinary tract;

(2) high biliary transport maxima (see G. Miller et al.,

Schweiz. med. Wochenschrift 99, 577-581, 1968);

(3) consistent visualization of the bile ducts;

(4) low toxicity, particularly when measured by intravenous injection intest animals, the toxicity of the intravenously administered compoundsbeing a more reliable and reproducible measure of physiologicaltolerance than the toxicity determined after administration through thegastrointestinal system;

(5) rapid excretion without residuals in the intestine;

(6) low nephrotoxicity;

(7) convenient synthesis in high yield and high purity,

more specifically, avoidance of the formation of isomers which requireto be separated.

It has been found that the requirements enumerated above are met to adegree not available heretofore by compounds which are acids of theformula or physiologically tolerated and non-toxic salts of such acidswith metals or amines, in the formula R being acetyl or propionyl, Rbeing methyl or ethyl, and n being an integer between 2 and 4.3-[2-(3-Acetylamino-2,4,6-triiodophenoxy)-ethoxy]-2-ethylpropionic acidand its salts are distinctly superior to the homologs of the aboveformula. The compounds of the invention differ from all pre- ICC.

viously known radiopaque compounds of similar chemical structure by theionizable terminal group and it appears that this terminal group is ofsignificant importance for ensuring the favorable properties of thecompounds.

The superiority of 3-[2-(3-acetylamino-2,4,6-triiodophenoxy)-ethoxy]-2ethylpropionic acid, its homologs within the limits of Formula (I), andof the corresponding salts will be apparent from the following Table ofresults obtained in comparison tests with the two orally administeredradiopaque compounds most widely used heretofore, iopanoic acid andipodate, and with radiopaque compounds closely related to the compoundsof the instant invention by their chemical structure, yet lacking theterminal group of Formula (II).

The Table includes data on biliary transport maxima which are indicativeof contrast in the representation of the gall bladder and associatedorgans. The data were determined in dogs by the technique of Rosati etal. (Investigative Radiology, 5, No. 4, 232, 1970).

The toxicity of the tested compounds was determined in rats (R) and mice(M) in oral and intravenous application and is expressed as L-D in theusual manner.

Hoppes Index was determined by actual cholecystography in dogs (1) andin cats (2) after oral administration of the tested compounds in adosage of ing/kg. (a) and/or 200 rug/kg. (b). On Hoppes scale (J. Amer.Pharm. Assoc. Sci. Ed. 48, 368-379, 1959), the density of the X-rayshadow and the contrast quality are expressed as 0 (negative), 1 (weak),2 (adequate), 3 (good), or 4 (excellent).

The visualization of the bile ducts in the animals employed fordetermining Hoppes index is recorded in the Table for some of the testedcompounds on a scale in which indicates no visibility or only occasionalvisibility, (-l) indicates visibility in all tests, and indicatesoptimum visibility with good details.

Additional explanations of the Table are found in footnotes.

The tested compounds are identified in the Table and elsewhere in thisspecification by capital letters as follows:

All tests were performed under uniform conditions and are directlycomparable. 20% suspensions of the acids were prepared with gum arabicand were administered to the test animals by means of a stomach tube inthe determination of Hoppes Index and of oral toxicity. Salts withsodium or N-methylglucamine, which are physiologically equivalent, wereemployed in determining toxicity by intravenous injection.

TABLE [Part 1] Bil. transp. Toxicity LDs mgJkg. max., Bile micromole}Compound Oral Intraven. ducts kgJmin.

R: 3,800.-- 13-.-- M: 5,200... O M: 3,700.-- D M: 2,200--- E M:2,800 F{M; 1,600..- seat-- G "ihI tlz 558570... E "{R: 2,500- I M: 9,800---[Part 2] Animal and Compound dosage 19 As determined by the technique ofW. Segerer (dissertation, Munich,

Maximum not entirely reached, because some animals died from higherdosage.

As is evident from the Table, the compounds of the invention comparefavorably in their toxicity with all tested known compounds, and areinferior in this respect only to Compound I which is not absorbed fromthe intestine in significant amounts and is not suitable forcholecystography, as is indicated by the minimal values of Hoppes Index.

The ratio of LD (oral) to LD (intravenous) is a measure of the rate atwhich a compound is absorbed from the intestinal tract into the bloodstream. A low ratio is indicative of rapid absorption. The respectiveratios for Compounds A, F, G, H, and I, as calculated from toxicityvalues for mice in the Table, are 2.4, 3.9, 5.4, 3.6, and 6.6, and showthe exceptionally rapid absorption of Compound A from the intestinaltract in good agreement with the observed absence of intestinal residuesand the lack of absorption of Compound I which is still found in theintestine after 24 hours. The toxicity values determined in rats andlisted in the Table show a corresponding superiority of Compound A.

All compounds of the invention (A-E) are consistently superior in theirHoppe Index values to the known compounds G and H which have been inclinical use for a long time, and compound A is significantly superiorto all other compounds tested, as would be expected from the very highvalues of biliary transport maxima. Compound I is not useful forcholecystography.

As not specifically stated in the Table, Compound A is superior to eachof Compounds F, G, and H in the ratio of the amounts secreted with thebile to the amounts secreted with the urine, and the nephrotoxicity ofCompound A is significantly lower than that of iopanoic acid.

In the attached drawing, the results of additional comparison tests ofCompound A with other radiopaque compounds are graphically illustrated.

The several curves are labeled with the capital letters assigned to thecompounds in the Table, and with A-Na etc. where the sodium salts wereempolyed.

FIG. 1 illustrates concentrations of radiopaque compounds in the bloodof dogs as a function of time after oral administration; and

FIG. 2 shows the percentage of radiopaque compounds secreted with thebile three hours after intravenous administration to rats as a functionof injected dosage.

The concentrations in FIG. 1 are expressed in micromole per milliliterafter oral administration of 148.5 micromole per kg. (56.57 mg. I perkg. body weight). The values were calculated by the method of the Latinsquare (5x5). A high initial value combined with rapid decrease isindicative of rapid absorption from the intestine and rapid secretion bythe liver.

The dosage values of FIG. 2 are expressed in mg. per kg. body weight.

The outstanding ability of Compound A to be excreted rapidly even athigh dosage rates is evident.

Because of the absence of an alkyl group attached to nitrogen inposition 3 of the triiodophenol radical of Compound A, geometric isomerscannot be formed during synthesis, and the pure compound is readilyobtained in high yields without the need for removal of unwantedisomers.

Compound A is the first known, orally administered contrast agent whichconsistently shows the bile ducts in radiographs. The bile ducts couldbe shown with certainty heretofore only by intravenous injection ofradiopaque compounds, a relatively hazardous procedure.

Because of its very low toxicity, the rapid absorption, and theresulting absence of intestinal residues, Compound A can be employedsafely and effectively at higher dosage rates than the known contrastagents, and X-ray images of high contrast are readily and safelyproduced.

The compounds of the invention are equally effective in the form of thefree acids and in the form of non-toxic and otherwise physiologicallytolerated ionizable salts. The sodium, lithium, calcium, and magnesiumsalts are typical of the metal salts of the invention, and alkanolaminesare the preferred, salt-forming amines. N-methylglucamine,N-rnethylxylamine (l-methylamino-l-desoxy- D-xylitol),l-methylaminopropanediol, and diethanolamine are representativealkanolarnines, but others will readily suggest themselves to thoseskilled in the art. The several metal and amine salts may be usedindividually or mixed as may be convenient and desired.

The compounds of the invention are prepared by methods which involvereactions of a 3-acylamino-2,4,6-triiodophenol with a reactivederivative of a 3-alkoxy-2- alkylpropionic acid having the formula R(III) wherein X is the reactive radical of a strong acid, that is,halogen, more specifically chlorine, bromine, or iodine, or a sulfate orsulfonate radical, R is hydrogen or alkyl, and n and R' are as definedabove. In this reaction, an ether is formed by elimination of X from thecompound of formula (III), the remainder of the compound being bound tothe oxygen of the phenol in the 3-acylamino- 2,4,6-triiodophenol. Theacyl group of the latter is identical with R in formula (I). The desired3-[(3-acylamino- 2,4,6-triiodophenoxy)-alkoxy]-2-alkylpropionic acid isrecovered from the reaction mixture in one or more steps.

A basic condensation agent, such as an alkali metal alcoholate or analkali metal carbonate, may be employed in the formation of the ether,or the 3-acylamino-2,4,6- triiodophenol is employed in the form of itssodium salt.

When R in formula (III) is alkyl, the ether obtained is an alkyl esterwhich is saponified prior to recovery of the desired acid or salt.3-(Alkylsulfonyloxyor arylsulfonyloxy-alkoxy)-2-alkylpropionic acidalkyl esters or 3- haloalkoxy-Z-alkylpropionic acid alkyl esters are themost conveniently employed starting materials.

The following Examples are further illustrative of this invention.

EXAMPLE 1 3- 2- (3-Acetylamino-2,4,6-triiodophenoxy) -ethoxy] -2-ethylpropionic acid (Compound A) A solution of 192 g.(3-acetylamino-2,4,6-triiodophenol sodium (0.35 mole) in 350 ml.dimethylacetamide, was mixed with 107.5 g.3-(2-iodoethoxy)-2-ethylpropionic acid ethyl ester (0.35 mole) at 90 C.with stirring over a period of about 30 minutes. Stirring was continuedwhile the mixture was held at 95 l00 C. for 16 hours. The solvent wasthen removed by distillation in a vacuum, and the residue was pouredinto 4000 ml. water. The solid precipitate formed was recovered andwashed with water, dilute sodium carbonate solution, dilute sodiumbisulfite solution, and again with much water. The ethyl ester ofCompound A was obtained in a yield of 220 g. (90%). When recrystallizedfrom 75% aqueous ethanol, it melted at 8086 C., and its thin layerchromatogram on silica gel with chloroform/glacial acetic acid 19/1 gavean R value of 0.57. The ester was identified by elementary analysis:

Calculated for C1'1H22I3NO'5: C, 29.12%; I, 54.31% Found: C, 29.15%; I,54.53%

The ester (70 g., 0.1 mole) was saponified in a boiling mixture of 250ml. methanol and 250 ml. water to which 100 ml. N sodium hydroxidesolution was added in small batches with stirring. The methanol wasdistilled from the saponification mixture, the residue was mixed withwater and extracted with ethyl acetate. The aqueous phase was acidifiedwith hydrochloric acid in the presence of sodium bisulfite.

The free acid (Compound A) gradually crystallized from the acidifiedsolution in the amount of 42.4 g. (63% yield). When recrystallized from50% ethanol and from ethyl acetate, it melted at 130 C. The R value of athin layer chromatogram prepared on silica gel with chloro form/aceticacid 19/1 was 0.32

The acid is insoluble in water, soluble in chloroform, and readilysoluble in methanol and ethanol. Its sodium salt dissolves in water at20 C. at a rate of 50 g. per 100 ml., and the N-methylglucamine salt issoluble at 20 in an equal weight of water. The salts were prepared bymixing solutions of equimolecular amounts of acid and base in a commonsolvent, such as methanol, and evaporating the solvent. The salts withethanolamine and other alkanolamines were prepared in an analogousmanner, Whereas the calcium and magnesium salts and nontoxic salts ofother metals were prepared from aqueous dispersions of the acids andbases by stirring at temperatures of about 4050 C., and evaporation ofthe water in a vacuum.

The 3-(2-iodoethoxy)-2-ethylpropionic acid ethyl ester was prepared inthe following sequence of steps:

0.8 Mole ethylmalonic acid diethyl ester was reacted in ether solutionwith 0.84 mole sodium hydride, and thereafter with 0.8 mole2-chloroethoxy-methyl chloride. 2-(2- Chloroethoxymethyl)-2-ethylmalonicacid diethyl ester was recovered as a liquid boiling at 136-144 C./4 mm.Hg.

0.47 Mole 2 (2-chloroethoxymethyl)-2-ethylmalonic acid diethyl ester waspartly saponified in 500 ml. 60% aqueous methanol with 0.5 mole sodiumhydroxide within two hours at 60 to 65 C. The methanol was evaporated,and the residue was acidified and extracted with ethyl to produce2-(2-chloroethoxymethyl)-2-ethylmalonic acid monoethyl ester which wasdecarboxylated by heating at 140150 C. The3-(2-chloroethoxy)-2-ethylpropionic acid ethyl ester formed thereby wasisolated, and it boiled at 119-124 C./4 mm. Hg.

0.325 Mole 3-(Z-chloroethoxy)-2-ethylpropionic acid ethyl ester wasrefluxed for 16 hours with 0.65 mole sodium iodide in 300 ml. ethanol,and the 3-(2-iodoethoxy)-2-ethylpropionic acid ethyl ester was recovered6 as a liquid boiling at 128 C./3-4 mm. Hg. It had an index ofrefraction n of 1.482.

The following additional methods also produced the ethyl ester ofCompound A and the free acid.

EXAMPLE 2 22 g. 3-acetylamino-2,4,6-triiodophenol sodium dissolved in 40ml. dimethylformamide was mixed gradually over a period of 10 minuteswith 9.2 g. 3-(2-chloroethoxy)-2-ethylpropionic acid ethyl ester, andthe mixture was stirred 20 hours at 110 C. to produce the ethyl ester ofCompound A. The ester was recovered as described in Example 1 andsaponified to produce the free acid which was obtained in an amount of15.2 g. (56.5% yield).

The etherification reaction in the first step of this procedure can beaccelerated somewhat by adding 5-7 g. sodium iodide.

The other lower alkyl esters of 3-(2-iodoethoxy)-2- ethylpropionic acidand 3-(2-chloroethoxy)-2-ethylpro pionic acid may be substituted for theafore-described ethyl esters in equimolecular amounts, the nature of thealcohol moiety being without significant effect on the reaction with thephenolate. The methyl, propyl, isopro pyl, and butyl esters are mostreadily available and equivalent to the ethyl ester, but other loweralkyl esters having up to five carbon atoms may be used instead.

EXAMPLE 3 14.7 g. 3-acetylamino-2,4,6-triiodophenol, 8.6 g. 3 (2-iodoethoxy)-2-ethylpropionic acid ethyl ester, and 0.037 mole sodiumethylate were heated 40 hours in 35 ml. ethanol to refluxing temperatureto produce the ethyl ester of Compound A which was recovered andsaponified in the manner described in Example 1 to produce 10.2 g.Compound A (54.5% yield).

Similarly, a mixture of 14.7 g. 3-acetylamino2,4,6-triiodophenol, 8.6 g.3-(2-iodoethoxy)-2-ethylpropionic acid, ml. methylethylketone, and 9 g.anhydrous potassium carbonate was refluxed for about 30 40 hours withagitation to produce the ethyl ester of Compound A which was convertedto 9.6 g. of the free acid in the afore-described manner (51.3% yield).

EXAMPLE 4 A solution of 275.5 g. 3-acetylamino-2,4,6-triiodophenolsodium (0.5 mole) in 600 ml. absolute ethanol was mixed by stirring withgradually added 181.7 g. 3-(2-benzenesulfonyloxyethoxy)-2-ethylpropionicacid ethyl ester (0.55 mole), and the mixture was kept at boilingtemperature for about five hours. One half of the solvent present wasdistilled off at ambient pressure, and the residue was stirred into fourliters water, adjusted to pH 6 by means of added acetic acid, andextracted with methylene chloride. The extract was Washed at 5 C. withdilute sodium carbonate solution and Water, and dried, and the anhydrousextract was evaporated to dryness.

The ethyl ester of Compound A was obtained as a residue weighing 334 g.(95% yield). When recrystallized from isopropanol or aqueous ethanol, itmelted at 85 86 C., and was saponified to the free Compound A asdescribed in Example 1.

The 3-(2-benzenesulfonyloxyethoxy) 2-ethylpropionic acid employed as astarting material Was prepared by reacting3-(2-iodoethoxy)-2-ethylpropionic acid ethyl ester with the silver saltof benzenesulfonic acid in acetonitrile. The intermediate so obtained isa viscous liquid not capable of being distilled without decomposition.

Procedures analogous to those described above were employed in producingadditional homologs of Compound A, however, none of the several homologswere superior nor even equal to Compound A in the properties essentialto a contrast agent for cholecystography.

7 EXAMPLE 3- [2-( 3-Acetylamino-2,4,6-triiodophenoxy) -etl1oxy]Z-methylpropionic acid (Compound B) A solution of 165 g.3-acetylamino-2,4,6-triiodophenol sodium (0.3 mole) in 350 ml.dimethylacetamide was reacted with 83.5 g.3-(2-iodoethoxy)-2-methylpropionic acid ethyl ester (0.3 mole) accordingto the procedure of Example 1. The ethyl ester of Compound B wasobtained in an amount of 192 g. (93% yield). When recrystallized fromethyl acetate, it had a melting point of 125 C. and an R value of 0.54on silica gel with chloroform/ glacial acetic acid 19/1. It wasidentified by elementary analysis:

Calculated for C H I NO C, 27.97%; I, 55.42% Found: C, 27.77%; I, 55.85%

134.4 g. Ethyl ester (0.2 mole) was saponified in boiling 35% aqueousmethanol with 52 ml. 4 N sodium hydroxide, and the free acid (CompoundB) was recovered from the saponification mixture as in Example 1 in anamount of 119 g. (90% yield). When recrystallized from ethyl acetate, itmelted out 151 C. and had an R value of 0.34 on silica gel withchloroform/glacial acetic acid 19/ 1.

The free acid is insoluble in water, soluble in chloroform, and readilysoluble in methanol and ethanol. Its sodium and N-methylglucamine saltswere prepared as described in Example 1 and dissolve in 100 ml. water at20 C. in respective amounts of 30 and 60 g.

The 3-(2-iodoethoxy)-2-methylpropionic acid ethyl ester was prepared inthe same manner in which the higher homolog had been prepared in Example1.

140 g. Methylmalonic acid diethyl ester was reacted with 20 g. sodiumhydride and with 103.2 g. 2-chloroethoxymethyl chloride to produce 118.7g. 2-(2-chloroethoxymethyl)-2-methylmalonic acid diethyl ester which hada boiling point of l32139 C. at 4 mm. Hg.

When 267 g. of the diethyl ester so obtained was partly saponified with42 g. sodium hydroxide, and the resulting monoethyl ester wasdecarboxylated, 103 g. 3-(2- chloroethoxy)-2-methylpropionic acid ethylester of hp. 102105 C./14 mm. Hg was recovered. From 93 g. of thelast-mentioned compound, 98 g. 3-(2-iodoethoxy)2- methylpropionic acidethyl ester boiling at 119 C./35 mm. Hg was formed by reaction with 144g. sodium iodide.

EXAMPLE 6 3- 3- 3-Acetylamino-2,4,6-triiodophenoxy) propoxy]2-ethylpropionic acid (Compound C) 38.5 g.3-Acetylamino-2,4,6-triiodophenol sodium in 80 ml. dimethylformamide wasreacted with 34.1 g. 5-(3- iodopropoxy)-2-ethylpropionic acid ethylester at 70 C. in 16 hours with agitation. The crude material wasrecovered by the method of Example 1 and dissolved in ethyl acetate. Thesolution was washed in sequence with sodium carbonate solution, Water,sodium bisulfite solution, and water, dehydrated with sodium sulfate,and evaporated. The amorpous residue was crystallized from 70% ethanolfor a yield of 37.5 g. (75%). The ethyl ester of Compound C thusobtained melted at 81-82 C., and had an R value of-( ).5 3 in a thinlayer chromatogram on silica gel with benzene/chloroform/acetic acid7/3/2.

26.9 g. Ethyl ester was saponified by boiling for about 5 hours in 150ml. ethanol and 60 ml. water in the presence of 41 ml. N sodiumhydroxide solution. The crude acid was recovered as in Example 1. Itmelted at 77-- 80 C. and was taken up in about 75 ml. boiling ethylacetate in which it dissolved completely, but from which the highermelting stable modification soon crystallized.

til

8 It melted at 135-137 C. in an amount of 17 g. (64% yield).

Compound C was identified by its elementary analysis:

Calculated for C H I NO C, 27.97%; I, 55.42% Found: C, 2809%; I, 55.64%

The thin layer chromatogram on silica gel with benzene/ chloroform/glacial acetic acid 7/ 3/ 2 gave an R; value of 0.46.

The free acid is sparingly soluble in water, but is soluble in 2.5weights ethanol, 7 weights ethanol, or about 10 weights boilingchloroform per one weight of the acid. The sodium salt dissolves inwater at 20 C. at a rate of 50 g. per ml., and the N-methylglucaminesalt at 100 g. per 100 ml.

The 3-(3-iodopropoxy)-2-ethylpropionic acid ethyl ester was preparedfrom ethylmalonic acid in the manner described above with reference tothe 3-(2-iodoethoxy)- 2-ethylpropionic acid ethyl ester fromethylmalonic acid diethyl ester by way of intermediates as follows:

'2-(3-chloropropoxymethyl)-2-ethylma1onic acid diethyl ester (b.p.142-148 C./2 mm. Hg, n =1.443)

3-(3-chloropropoxy)-2-ethylpropionic acid ethyl ester (b.p. 103 -107C./2 mm. Hg, n =1.438)

3-(3-iodopropoxy)-2-ethylproponic acid ethyl ester (b.p.

-127 C./2 mm. Hg, 21 1.478)

EXAMPLE 7 3- [4- 3-Acetylamino-2,4,6-triiodophenoxy)butoxy]-2-ethylpropionic acid (Compound D) The method of Example 6 wasemployed for reacting 27.5 g. 3-acetylamino-2,4,6-triiodophenol sodiumwith 17.3 g. 3-(4-iodobutoxy)-2-ethylpropionic acid ethyl ester in 60ml. dimethylformamide. The resulting amorphous ethyl ester of Compound Dwas saponified as in Example 6 and converted to the crystalline CompoundD which melts at approximately 120 C. and has an R value of 0.43 onsilica gel with benzene/chloroform/ glacial acetic acid 7/3/2. It wasidentified by elementary analysis:

Calculated for C1'7H22I3NO5I C, 29.12%; I, 54.31% Found: C, 29.16%; I,53.99%

The free acid is practically insoluble in water even at a boil, but issoluble in about 40 times its weight of cold chloroform, 10 times itsweight of hot chloroform, and approximately 7 weights of cold ethanol,and is very soluble in methanol and in boiling ethanol. 100 Ml. water at20 C. dissolves 30 g. of the sodium salt or 25 g. of theN-methylglucamine salt.

The 3-(4-iodobutoxy)-2-ethylpropionic acid ethyl ester was prepared fromethylmalonic acid diethyl ester in a manner analogous to theafore-described synthesis of its homologs. The following compounds wereobtained in the several steps:

2-(4-chlorobutoxymethyl)-2-ethylmalonic acid diethyl ester (b.p. 155C./2 mm. Hg; n =1.446

3-(4-chlorobutoxy)-2-ethylpropionic acid ethyl ester (b.p.

117l24 C./2 mm. Hg, n =1.438)

3-(4-iodobutoxy)-2-ethylpropionic acid ethyl ester (b.p.

137-142 C./2 mm. Hg; n =1.475)

EXAMPLE 8 3- [2- 3-Propionylamino-2,4,6-triiodophenoxy ethoxy]-2-ethylpropionic acid (Compound E) The ethyl ester of Compound E wasprepared from 16.95 3-propionylamino-2,4,6-triodophenol sodium (0.3

mole) and 10 g. 3-(2-iodoethoxy)-2-ethylpropionic acid ethyl ester(0.032 mole) by reaction in 30 ml. dimethylformamide at 90 C. as inExample 1 in an amount of 15.2 g. (71% yield). When recrystallized fromethyl acetate, the ester melted at 86 C. and had an R, value of 0.65 ina thin layer chromatogram on silica gel with benzene/ chloroform/glacial acetic acid 7/ 3/ 2.

Calculated for C H I NO C, 30.23%; I, 53.24% Found: C, 30.38%; I, 52.94%

The free acid (Compound E) was obtained by saponification of the ethylester as in Example 1 and melted at 114 C. when recrystallized fromethyl acetate. It had an R; value of 0.70 in a thin layer chromatogramon silica gel with benzene/chloroform/glacial acetic acid 7/3/2. Theacid was identified by elementary analysis:

Calculated fOr C H I NO C, 27.97%; I, 55.42% Found: C, 28.12%; I, 55.39%

Compound E is insoluble in water, but dissolves freely in chloroform,methanol, and ethanol. The sodium salt dissolves in water of 20 C. at arate of 10 g./100 ml., and the analogous solubility of theN-methylglucamine salt is 50 g./100 ml.

EXAMPLE 9 3- [2- 3-Propyionylamino-2,4,6-triiodophenoxy ethoxy]-2-methylpropionic acid The ethyl ester was prepared in a manner obviousfrom Example 8 and had a melting point of 79 C. when recrystallized froma 2:1 (vol.) mixture of ethanol and water, and had an R; value of 0.56in a thin layer chromatogram on silica gel with benzene/ chloroform/glacial acetic acid 7/3/2. It was identified by its elementary analysis:

Calculated for C H I NO C, 29.12%; I, 54.31% Found: C, 29.40%; I, 54.19%

The free acid obtained by saponification of the ester melted at 145 C.when recrystallized from ethyl acetate and had an R value of 0.68 in athin layer chromatogram on silica gel with benzene/chloroform/glacialacetic acid 7/3/2.

Calculated for C H I NO C, 26.77%; I, 56.57% Found: C, 27.00%; I, 56.19%

The following additional compounds were prepared by interchangingreactants and substituents in the procedures described above:

The afore-described compounds of the invention may be combined withsuitable excipients conventional in ga lenic pharmacy for administrationprior to cholecysteography. Those skilled in the art will readilyformulate X- ray contrast compositions containing the compounds of theinvention as radiopaque ingredients, and produce capsules, granulates,tablets, dragees, pellets, liquids for rectal application, andsuspensions or solutions for oral administration. It has been foundadvantageous orally to administer the radiopaque compounds of theinvention in the micronized condition in which they are absorbed mostreadily and produce denser images of the gall bladder and associatedorgans without leaving radiopaque residues in the intestinal tract.

Radiopaque compositions of the invention may contain the novel compoundseither in the form of the free acids or as salts with metals and amineswhich are physiologically tolerated and non-toxic in the relativelylarge doses required. The following Examples illustrate methods ofpreparing compositions for oral administration which contain thecompounds of the invention as the sole active agents.

EXAMPLE 10 300 g. Compound A was micronized to a particle size smallerthan 4 microns and intimately mixed with 20.4 g. of Pluronic F68, anormally solid surfactant which is a condensation product of ethyleneoxide and polypropylene glycol and prevents agglomeration of themicronized particles. The dual mixture was sieved through a stainlesssteel Wire screen having 324 openings per square centimeter and furthermixed with 20.4 g. microcrystalline starch.

The ternary mixture was moistened with distilled water and granulated bypassage through a screen having 56 openings per square centimeter intoan air stream at 40 C. The granules were coated with 7.2 g. of magnesiumstearate and distributed uniformly in 600 soft gelatin capsules whicheach received 500 mg. of the active agent.

Granules prepared in the same manner were converted to drages by coatingin a kettle with syrup at a ratio of 4:1, as is conventional. The dragesso obtained were mixed.

EXAMPLE 11 5 kg. Compound A and 2 liters starch paste containing g. cornstarch were worked into a homogeneous dough on a kneading machine, and alittle dry starch was added to the moist mixture to reduce itstackiness. It was then granulated and dried in a vacuum. The granulatewas further mixed with 0.5 kg. corn starch and 25 g. magnesium stearateand tabletted, each tablet containing 500 mg. of Compound A.

EXAMPLE 12 0.75 kg. Granulated sugar (sucrose) and 5 kg. of the sodiumsalt of Compound A were mixed with 0.75 kg. corn starch. The mixture wasmoistened with 1000 ml. 50% aqueous ethanol and thereafter granulated.The granulate was dried, screened, further mixed with 0.65 kg. cornstarch, 0.05 kg. talcum, and 0.05 kg. magnesium stearate, and convertedto 10,000 tablets.

What is claimed is:

1. A compound which is a3-[(3-acylamino-2,4,6triiodophenoxy)-alkoxy]-2-alkylpropionic acid ofthe formula or a water-soluble salt of said acid with a physiologicallytolerated metal or amine, in said formula R being acetyl or propionyl, Rbeing methyl or ethyl, and n being an integer between 2 and 4.

1 1 1 2 2. A compound as set forth in claim 1 which is said ReferencesCited acid.

3. A compound as set forth in claim 1 which is a salt UNITED STATESPATENTS of said acid with an alkali metal, calcium, magnesium, 3,553,2591/1971 Felder et a1 260-419 or an alkanolamine.

4. A compound as set forth in claim 1, wherein R is 5 BERNARD HELENPrimary Examiner acetyl, R is ethyl and n is 2. M. W. GLYNN, AssistantExaminer 5. A compound as set forth in claim 4, which is said acid. US.Cl. X.R.

6. A compound as set forth in claim 4, is a salt 10 P R R P of said acidwith sodium or N-methylglucamine.

1. A COMPOUND WHICH IS A3-(3-ACYAMINO-2,4,6-TRIIODOPHENOXY)-ALKOXY)-2-ALKYLPROPIONIC ACID OF THEFORMULA